Variant: NM_001100.4(ACTA1):c.217dup (p.Ile73fs)

CA915942047

817462 (ClinVar)

Gene: ACTA1

Condition: alpha-actinopathy

Inheritance Mode: Autosomal recessive inheritance

UUID: e3f9ec67-adea-4393-8423-5bcc29d619bd

Approved on: 2024-08-07

Published on: 2024-12-19

HGVS expressions

NM_001100.4:c.217dup
NM_001100.4(ACTA1):c.217dup (p.Ile73fs)
NC_000001.11:g.229432793dup
CM000663.2:g.229432793dup
NC_000001.10:g.229568540dup
CM000663.1:g.229568540dup
NC_000001.9:g.227635163dup
NG_006672.1:g.6304dup
ENST00000366683.4:c.217dup
ENST00000684723.1:c.82dup
ENST00000366683.3:c.217dup
ENST00000366684.7:c.217dup
NM_001100.3:c.217dup

Pathogenic

• Met criteria codes: PM2_Supporting PM3 PVS1

• Not Met criteria codes: PS4

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 1.0.0

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_001100.4:c.217dup (p.Ile73fs*11) variant in ACTA1 is a frameshift variant that is expected to result in nonsense-mediated mRNA decay and is present in biologically-relevant transcripts (PVS1). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). There is no published data on this variant, however Invitae has reported the variant in one proband, who presented with hypotonia (SCV001201868.3). In addition, this proband carried the variant of interest in trans with a second ACTA1 variant c.782A>T (p.Glu261Val) that has been classified as pathogenic at Invitae (PM3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha-actinopathy. ACMG/AMP criteria met, as specified by the congenital myopathies VCEP: PVS1, PM2_Supporting, PM3 (ClinGen Congenital Myopathies VCEP specifications version 1; 08/07/2024).

Met criteria codes

• PM2_Supporting: The variant is absent from gnomAD v4.1.0 with adequate genome and exome coverage, meeting PM2_Supporting criteria.
• PM3: The proband carried the variant of interest in trans with a second ACTA1 variant c.782A>T (p.Glu261Val) that has been classified as pathogenic at Invitae.
• PVS1: The variant is a frameshift variant that is predicted to undergo nonsense-mediated mRNA decay and is present in biologically-relevant transcripts

Not Met criteria codes

• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline